ACUTE LYMPHOBLASTIC LEUKEMIA

PROF.S.TITO’S UNIT M5

DR.M.ARIVUMANI

Acute lymphoblastic leuKemia is malignant disease of marrow in which early lymphoid precursors proliferate and replace the normal haematopoietic cells

Normal marrow

Entire marrow replaced by blast

Marrow showing blasts

Relative frequencies of lymphoid malignancies

NHL(62.4%)

• Epidemiology peaK incidence in 2 to 6 years more in boys than girls. median age in adults-35years• Etiology less studied environmental and genetic factors

Chromosomal abnormalities in ALL

ABNORMALITIES ADULTS(%) CHILDREN(%)

Normal karyotype 16-34 9

hypodiploidy 4-9 1

hyperdiploidy 2-9 25

t (9;22) 11-30 4

t (4;11) 3-7 6

t (10;14) 4-6 4

t (8;14) 4 2

t ( 1;19) 3 5

9p abnormality 5-16 7-13

6q abnormality 2-6 4-6

12p abnormality 4-5 22

Factors predisposing ALL

GENETIC ENVRONMENTAL

Downs,turner, klinefelter Ionising radiation

Fanconi,diamond blackfan Drugs

NF Type1 alkylating agents

Ataxia telengiectasia nitrosourea

SCID epipodophyllotoxin

PNH benzene exposure

Li-fraumeni syndrome advanced maternal age

Blooms syndrome paternal smoking

FAB CLASSIFICATION OF ALL

CYTOLOGIC FEATURES

L1 L2 L3

Cell size Small cells predominate,homogenous

Large,heterogenous in size

Large homogenous

cytoplasm Scanty Variable,often moderately abundant

Moderately abundant

nucleoli Small One or more,often large

One or more,prominent

Nuclear shape Homogenous Variable, heterogenous

Stippled, homogenous

Nuclear shape Regular Irregular clefts regular

Cyt.basophilia variable variable Intensely basophilic

Cyt.vacuolation variable variable prominent

Immunologic subtype

% of cases FAB subtype Cytogenetic abnormalites

Pre B ALL 75 L1,L2 t(9;22),t(4;11)t(1;19)

Tcell ALL 20 L1,L2 14q11 or 7q34

Mature Bcell ALL(burkitt leukemia)

5 L3 t(8;14)

Classification of ALL(WHO)

Pre B ALL(L1)Small blasts wth thin rim of cytoplasm

T Cell ALL(L1)

T Cell ALL (L2)Irregular clefts of nucleus

Burkitt leukemia-Mature B Cell ALL(L3)-vacuolations

CNS Leukemia(csf showing blasts)

B Cell ALL (85%)type tdt CALLA Surface Ig

Early pro B ALL positive negative negative

Pre Bcell ALL positive positive negative

Mature B ALL negative positive positive

T Cell ALL(15%)

• Early subtype• CD3 -, CD4-,CD8- or• CD3-,CD4+,CD8+.• Later subtype• CD3+ with CD4+ or CD8+

T Cell ALL(CD3 Positive)

CLINICAL FEATURES

Due to infiltration of marrow• SYMPTOMS Due to decreased production of normal marrow elements

Symptoms symptoms percentage

fatigue 92

Bone or joint pain 79

fever 71

Weight loss 66

Abnormal masses 62

purpura 51

Other haemorrhage 27

infection 17

Physical findings

Physical findings percentage

splenomegaly 86

lymphadenopathy 76

hepatomegaly 74

Sternal tenderness 69

purpura 50

Fundic changes 14

Investigations

CBC-Anemia,thrombocytopenia,leucopenia or leucocytosis.

Peripheral smear study-circulating blast can be seen.

Confirmatory Bone marrow aspiration/biopsy

Bone marrow biopsy(gross specimen)

Criteria for diagnosis

• Bone marrow or peripheral smear showing

Aleast 30% blast(FAB) Atleast 20%blast (WHO)MPO Negative,tdt positive is hallmark

ofLymphoblast,however in L3 tdt is

negative

Investigation (cont)

• Cytogenetics.• Flow cytometry.

Investigation (cont)

• LDH,Serum uric acid• Coagulation profile• LFT,RFT• Chest xray,CT chest• Blood culture• Baseline Echo,ECG

TreatmentPre Chemotherapy supportive careChemotherapy Preinduction Remission induction-phase 1 & 2 Reinduction CNS preventive therapy consolidation Maintenance therapyAllogenic stem cell transplantationNewer drugsSupportive careTreatment of relapseEffects of treatment

Supportive care

Treat metabolic complications hyperuricemia-hydration,rasburicase hyperphosphatemia-po4 binders hypocalcemia-Ca supplements Hyperleuckocytosis-leukopharesis Infection control-broad spectrum

antibiotics Hematologic support

Preinduction

• Prednisolone 1mg/kg p.ofor 5 days • Recheck blast after 5 days, if blast

count dropped-good response.

Treatment of ALLInduction 1

cycle chemotherapy Dose and schedule

Induction Prednisolone or 1mg/kg p.o days 1-28 days

vincristine 1.5mg/m2 i.v weekly one dose x 4 weeks

doxorubicin 30mg/m2 i.v weekly one dose x 4 weeks

L-Asparginase 1,00,000 u/m2(total dose) in divided doses of 10,000 u daily for 10 days

CNS Preventive therapy methotrexate 12mg IT days 1,8,15,22

Reassess

• After 4 weeks of phase 1 induction assess marrow for remission.

• If there is remission taper prednisolone

and after 1 week of restart phase2 induction,

• If there is no remission give 2 more weekly doses of vincristine and doxo and then assess, if still no remission go for alternate regimen.

Induction 2Induction2 drugs Dose and schedule

Cyclophosphamide

Cytosine arabinoside

650mg/m2 i.v days 1 and 1575mg/m2 i.v x 4 days a weeks for 4 weeki.e day 1-4,8-11,15-18,22-25

methotrexate 12mg/m2 IT days 1,8,15,22

Cranial radiation 200 cGy x 9days

ReinductionReinduction drug Dose and schedule

vincristine 1.5 mg/m2 i.v weekly one dose on day 1 and 8

doxorubicin 30mg/m2 i.v. weekly one dose on day 1 and 8

prednisolone 1mg/kg p.o daily for 14 days

consolidation consoldation drugs Dose and schedule

cyclophosphamide 750/m2 .i.v days 1 and 15

Cytosine arabinoside 75mg/m2 doses days 1-4 and 15-18

Maintenance phase duration- upto 2 years

maintenance drug Dose and schedule

1st month methotrexate 12.5mg i.t on day 1

vincristine 1.4mg/m2 .v day 1

prednisolone 1mg/kg p.o daily day 1-7

6 mercaptopurine 60mg/m2 p.o. daily for next 3 weeks

methotrexate 15mg/m2 p.o. once a week for 3 weeks.

2nd month 6 MCP and T.Methotxerate for 4 weeks.

Follow up

If the patient completes chemotherapy for 2 years without relapse-stop chemo and follow up.

No relapse within 5 years-can be declared as cured.

Refractory ALL

Allogenic stem cell transpantation

• Usually done in second remission.• Can be done in first remission in high

risk patients WBC>25000 philadelphia chromosome positive poor initial response to remission induction

Newer drugs

Monoclonal antibodies rituximab(CD20),epratuzumab(CD22) alemtuzumab(CD52),gemtuzumab(CD33)Antimetabolites clofarabine,nelarabineTyrosine kinase inhibitor imatinib,nilotinib,dasatinibVornistat,sirolimus,everolimus,oblimersen,

Late effects of treatment

Cranial irradiation-cognitive and intellectual impairment,cns neoplaysms

Chemotherapeutic drugs-secondary AMLEndorine dysfunctions-short

stature,obesity,growth retardationAnthracycline-cardiotoxicitySteroid-avascular necrosis of bone.

RelapseReappearance of blast at any site in the body after initial

remisson during chemotherapy or after comleting chemo.Marrow relapse-poor outcome Hyper CVAD regimen allogenic BM transplantCNS relapse -Triple IT –alternate days till csf clears,then

twice weekly 6 doses.then one dose every week 6 doses. - cranial irradiationTesticular relapse -chemotherapy plus b/l testicular radiation

Cns relapse

Prognostic factors in ALL

Determinants Favourable unfavourable

WBC Counts <10,000 >2,00,000

Age 2-10 years <1yr,>10yr

Gender female male

Ethnicity white blac

Node,liver,splenomegaly absent massive

Testicular enlargement absent present

CNS involvement absent Csf blast and pleocytosis

FAB Type L1 L2

Cytogenetics T(12;21)(TEL-AML1)Trsomies 4,10,17

t(9;22)(bcr-abl)t(4;11)(MLL-AF4)

Ploidy hyperdipoidy hypodiploidy

Time to remission <14days >28days

References. 1.Harrison’s principles of internal medicine 17th edition 2.Williams hematology 8th edition 3.Wintrobe’s clinical hematology 4.Nelson textbooK of paediatrics 5.ash.hematologylibrary.com/image bank.

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